【摘要】：上篇:乳香酸治療神經(jīng)病理性痛的作用及機制研究背景:神經(jīng)病理性疼痛(Neuropathic pain)是疼痛中最難治療、最為復雜的類型,嚴重危害人類身心健康,影響生活質(zhì)量,是當前神經(jīng)科學研究的熱點。神經(jīng)病理性痛發(fā)生發(fā)展機制及治療靶點尚未完全闡明,臨床尚無明顯有效的治療藥物和措施。目前應用于臨床的治療藥物和策略治療效果差強人意,且伴隨著眾多藥物副作用。因此,探索研發(fā)針對性治療藥物對神經(jīng)病理性疼痛的治療具有重要意義。神經(jīng)膠質(zhì)細胞炎性反應是神經(jīng)病理性疼痛產(chǎn)生和維持的關鍵。前期研究證實中藥乳香的最重要有效成分群乳香酸具有強大的抗炎和抗腫瘤作用,但尚未有研究闡述其對神經(jīng)病理性疼痛治療效果如何,本實驗擬探討乳香酸對神經(jīng)病理性疼痛的作用和機制,從而為神經(jīng)病理性疼痛針對性治療藥物的研發(fā)提供理論和實驗依據(jù)。方法:本研究基于小鼠坐骨神經(jīng)分支選擇性損傷模型(spared nerve injury,SNI)所誘導的神經(jīng)病理性痛,應用von Frey及熱刺激行為學測試,觀察口服給予乳香酸對小鼠基礎痛閾和SNI所致的神經(jīng)病理性痛的影響。通過免疫組織化學和Western blot檢測乳香酸對正常和SNI小鼠脊髓背角星形膠質(zhì)細胞活化的影響,以及p JNK表達的情況,通過ELISA檢測乳香酸對炎癥因子(IL-6、IL-1β和TNF-α)以及MCP-1表達變化的影響。結(jié)果:行為學結(jié)果顯示乳香酸劑量依賴性的降低SNI誘導的機械性痛覺敏感和熱痛覺敏感。結(jié)合免疫組織化學實驗結(jié)果和Western blot定量檢測結(jié)果發(fā)現(xiàn)乳香酸可以降低SNI誘導的星形膠質(zhì)細胞活化,降低纖維酸性蛋白(glial fibrillary acidic protein,GFAP)的表達。乳香酸可以劑量依賴性的抑制SNI誘導的星形膠質(zhì)細胞JNK通路的激活,以及炎癥因子(IL-6、IL-1β和TNF-α)和MCP-1的表達。結(jié)論:綜上所述,乳香酸通過抑制脊髓背角星形膠質(zhì)細胞內(nèi)JNK信號通路的活化,緩解由SNI誘導的神經(jīng)病理性痛。下篇:磷丙泊酚鈉-阿芬太尼協(xié)同鎮(zhèn)痛作用研究背景:臨床麻醉的主流趨勢是復合麻醉,即聯(lián)合使用兩種以上的麻醉藥物來達到理想效果的麻醉方式。復合麻醉以期幾種藥物同時使用時能夠產(chǎn)生協(xié)同作用,比如麻醉誘導更迅速,麻醉維持更平穩(wěn),不良反應更少,應用更安全。丙泊酚(Propofol)因其起效迅速、誘導平穩(wěn)、蘇醒快等優(yōu)點常和阿片類藥物應用于各類手術麻醉,但在臨床中發(fā)現(xiàn)丙泊酚存在呼吸抑制、注射痛以及丙泊酚輸注綜合征等不良反應。磷丙泊酚鈉(Fospropofol)是丙泊酚的一種水溶性前藥,靜脈注射之后幾分鐘內(nèi)代謝為活性藥物丙泊酚,磷丙泊酚鈉具有更好的安全性,更適用于那些不需要立刻起效但是需要維持時間較長的手術麻醉。磷丙泊酚鈉與阿片類藥物之間的相互作用研究鮮少有文獻報道。本實驗擬根據(jù)藥效學結(jié)論,采用等輻射分析的方法來驗證二者聯(lián)用是否能夠產(chǎn)生藥效的鎮(zhèn)痛協(xié)同效應,為研發(fā)具有鎮(zhèn)靜鎮(zhèn)痛作用的復合麻醉藥物提供理論和實驗依據(jù)。方法:本研究采用熱板法、熱輻射甩尾法和福爾馬林實驗研究磷丙泊酚鈉和阿芬太尼以及二者聯(lián)用的鎮(zhèn)痛作用。通過對數(shù)劑量效應曲線計算出磷丙泊酚鈉和阿芬太尼的鎮(zhèn)痛ED50,按照固定比例(1,1/2,1/4,1/8)物理混合兩藥,計算混合藥物的鎮(zhèn)痛ED50。應用等輻射分析法(Isobologrphic analysis)研究兩種藥物鎮(zhèn)痛相互作用。結(jié)果:在三種疼痛模型中磷丙泊酚鈉和阿芬太尼均可明顯緩解疼痛的發(fā)生,并呈劑量依賴性。通過等輻射分析法發(fā)現(xiàn)三種疼痛模型中的ED50mix均顯著小于ED50add(P0.05)相互作用指數(shù)γ均小于1。結(jié)論:綜上所述,磷丙泊酚鈉和阿芬太尼具有協(xié)同鎮(zhèn)痛作用,這為磷丙泊酚鈉-阿芬太尼復方制劑的研發(fā)提供了一定的理論依據(jù)。
[Abstract]:Previous: Neuropathy pain (Neuropathic Pain) is the most difficult to treat in pain. Neuropathy pain is the most difficult to treat in pain. It is the most complicated type, which seriously affects the physical and mental health of human and affects the quality of life. It is a hot spot in the research of the present neuroscience. The mechanism of the development of the neuropathic pain and the therapeutic target have not been fully set out, and there is no obvious and effective treatment of the drugs and measures in the clinic. The present invention is applied to the treatment of the medicine and the treatment effect of the strategy, and is accompanied by many side effects of the medicine. Therefore, it is of great significance to explore the treatment of neuropathic pain by research and development of targeted therapeutic drugs. The inflammatory response of glial cells is the key to the generation and maintenance of neuropathic pain. The preliminary study confirmed that the most important effective component group of the traditional Chinese medicine frankincense has strong anti-inflammatory and anti-tumor effects, but has not yet studied how to effect the treatment effect on the neuropathic pain, and the experiment is to explore the role and mechanism of the frankincense acid on the neuropathic pain, so as to provide a theoretical and experimental basis for the research and development of the drug for the treatment of the neuropathic pain. Methods: The effects of oral administration of boswellic acid on the base pain threshold of mice and the neuropathic pain caused by SNI were observed based on the neuropathic pain induced by the selective injury model (SNI) of the sciatic nerve of mice. The effect of boswellic acid on the activation of the dorsal horn of spinal cord in normal and SNI mice and the expression of p-JNK were detected by immunohistochemistry and Western blot, and the effect of the expression of frankincense on the inflammatory factors (IL-6, IL-1 and TNF-1) and the expression of MCP-1 was detected by ELISA. Results: The results of behavior show that the dose-dependent decrease of the dose-dependent mechanical hyperalgesia and thermal hyperalgesia induced by SNI. The results of immunohistochemistry and Western blot were used to detect the activation of the astrocyte induced by SNI and to decrease the expression of the fiber acidic protein (GFAP). The boswellic acid can inhibit the activation of the JNK pathway of the astrocytes induced by SNI and the expression of the inflammatory factors (IL-6, IL-1 and TNF-1) and MCP-1 in a dose-dependent manner. Conclusion: In conclusion, the activation of the JNK signaling pathway in the astrocytes of the spinal dorsal horn of the spinal cord is inhibited, and the neuropathic pain induced by the SNI is relieved. Background: The main trend of clinical anesthesia is compound anesthesia, that is, the combination of more than two kinds of narcotic drugs to achieve the desired effect. The compound anesthesia can produce a synergistic effect in the simultaneous use of several medicines, such as more rapid anesthesia induction, more stable and more stable anesthesia, less adverse reaction and safer application. Propanol has the advantages of rapid onset of action, stable induction and fast recovery, and the application of opioids in all kinds of surgical anesthesia, but it is found in the clinic that there are adverse reactions such as the respiratory depression, the injection pain, and the propofol infusion syndrome. Focopodool is a water-soluble pre-drug for propafenol, which is metabolically active in a few minutes after intravenous injection, which has better safety and is more suitable for those who do not need immediate action but require longer maintenance time. The study of the interaction between the sodium and the opioids is less and less reported. Based on the results of the pharmacodynamics, it is proposed to use the method of equal radiation analysis to verify whether the combination of the two drugs can produce the analgesic synergistic effect of the drug effect, and provides the theoretical and experimental basis for the research and development of the compound anesthetic drugs with the effects of sedation and analgesia. Methods: The analgesic effects of P-and-Fentanyl and Fentanyl were studied by hot plate method, heat radiation tail-throwing method and formalin test. The analgesic ED50 of P-and Fentanyl was calculated by the log-dose effect curve, and the analgesic ED50 of the mixed drug was calculated according to the fixed ratio (1, 1/ 2, 1/ 4, 1/ 8). Isothermal analysis was used to study the analgesic interaction of two drugs. Results: In the three pain models, both P-and Fentanyl could alleviate the occurrence of pain and dose-dependently. The ED50mix in the three pain models was significantly lower than that of ED50add (P0.05). Conclusion: To sum up, the co-analgesic effect of P-propafenone and Fentanyl is a theoretical basis for R & D of the compound preparation of P-propafenone and Fentanyl.
【學位授予單位】：第四軍醫(yī)大學
【學位級別】：碩士
【學位授予年份】：2016
【分類號】：R96

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